Project Summary

Trypanosomatidae such as African trypanosomes (prototype: Trypanosoma brucei) and Leishmania sp are flagellate protozoans that develop in insect vectors (the tsetse fly and sand fly, respectively) and can be transmitted to various mammals. They cause diseases such as human sleeping sickness or visceral leishmaniasis and are fatal if left untreated, representing a major challenge for public health programs. Despite their close evolutionary relationship, these parasites strongly differ in their physiology and mode of growth in mammalian host, being extracellular for T. brucei and intracellular for Leishmania. Both organisms share an efficient ability to adapt to the immune defence systems of their mammalian and insect vector hosts, hereby affecting the outcome of these neglected diseases.

During the previous phases of the IAP programme our consortium has contributed to understand several cellular and molecular mechanisms allowing T. brucei to adapt to different hosts, including the system of antigenic variation and the response of a T. brucei subspecies (T. b. rhodesiense) to counteract the specific innate defence of humans. These studies also led to a better knowledge of the insect and mammalian host immune reaction to the parasite, including parasite-driven alterations of the immune system to promote the development of parasitemia and tissue damage (pathogenicity) in mammalian host. Moreover, we showed that the parasite could impact on its transmission success by modifying the physiology of its insect vector.

We propose to build on this work to:

Study how African trypanosomes counteract the capacity of the (insect and mammalian) host to eliminate the pathogen (called resistance to infection).

Address how the host in turn attempts to control the tissue pathogenicity during parasite infection (called tolerance of the host to infection).

In addition, we intend to extend our research to the related parasite Leishmania donovani causing visceral leishmaniasis, aiming to benefit from this dual expertise to further study certain aspects of the biology of these parasites, such as their common resistance to the oxidative response of myeloid cells/macrophages and ability to cause tissue damage.